PROJECT SUMMARY Perinatal hypoxic-ischemic encephalopathy (HIE) is associated with high neonatal mortality and severe long-term neurologic morbidity. The molecular mechanisms and the pathway of brain injury in infants with HIE remain largely elusive. Although therapeutic hypothermia is the current standard of care for newborns with moderate to severe HIE, nearly half of affected infants treated with hypothermia still die or suffer significant neurologic disability. Thus, there is an urgent need to further investigate the underlying mechanisms and to develop additional treatment strategies. Recently, we discovered in an animal model of neonatal rats that hypoxic-ischemic (HI) insult significantly increased microRNA 210 (miR210) in the brain. Of particular importance, we found that inhibition of miR210 significantly reduced HI-induced brain injury and improved long-term neurobehavioral function recovery. MiR210 is The Master Hypoxamir of a specific group of miRs termed ?Hypoxamirs? that are regulated by hypoxia. MiRs are important players in the epigenetic control of gene expression, and silence gene expression by binding to 3?-untranslated region (3?UTR) of transcripts, resulting in transcript degradation or translational inhibition of the target genes. Recent studies have revealed an important role of miRs in the regulation of both innate and adaptive immune cell function. Neuroinflammation is a critical contributor to perinatal hypoxic- ischemic brain injury. Yet, the mechanisms of miRs in the regulation of neuroinflammation in neonatal hypoxic-ischemic brain injury remain unknown. Our preliminary studies demonstrated that hypoxic-ischemic insult activated microglia and increased pro-inflammatory cytokines and lymphocyte infiltration in the neonatal brain. Of importance, the preliminary data showed a potential role of miR210 in the regulation of inflammatory response in the brain, suggesting a highly novel mechanism of miR210-mediated neuroinflammation in perinatal hypoxic-ischemic brain injury. These exciting findings provide a strong scientific premise for us to move forward to explore mechanisms of miR210 in the understanding of perinatal hypoxic-ischemic brain injury. Thus, the proposed study will test the hypothesis that miR210 plays a key role in regulating neuroinflammation that contributes to perinatal hypoxic-ischemic brain injury. The outcome of the proposed study will have major impact in advancing our knowledge in the molecular mechanisms underlying perinatal hypoxic-ischemic brain injury, and provide new insights and a proof of concept in a novel target of epigenetic regulation in potential therapeutic strategies that may be beneficial for the treatment of infants with hypoxic-ischemic brain damage. This is of critical importance given the extreme limit of effective therapeutic intervention currently available other than hypothermia for this important clinical problem in newborns.